An exploratory, open-label, randomized, multicenter study to investigate the pharmacodynamics of a glycoengineered antibody (imgatuzumab) and cetuximab in patients with operable head and neck squamous cell carcinoma.

BACKGROUND: In addition to inhibiting epidermal growth factor receptor (EGFR) signaling, anti-EGFR antibodies of the IgG1 'subtype' can induce a complementary therapeutic effect through the induction of antibody-dependent cell-mediated cytotoxicity (ADCC). Glycoengineering of therapeutic antibodies increases the affinity for the Fc-gamma receptor, thereby enhancing ADCC. PATIENTS AND METHODS: We investigated the changes in immune effector cells and EGFR pathway biomarkers in 44 patients with operable, advanced stage head and neck squamous cell carcinoma treated with two preoperative doses of either glycoengineered imgatuzumab (GA201; 700 or 1400 mg) or cetuximab (standard dosing) in a neoadjuvant setting with paired pre- and post-treatment tumor biopsies. RESULTS: Significant antitumor activity was observed with both antibodies after just two infusions. Metabolic responses were seen in 23 (59.0%) patients overall. One imgatuzumab-treated patient (700 mg) achieved a 'pathological' complete response. An immediate and sustained decrease in peripheral natural killer cells was consistently observed with the first imgatuzumab infusion but not with cetuximab. The functionality of the remaining peripheral natural killer cells was maintained. Similarly, a pronounced increase in circulating cytokines was seen following the first infusion of imgatuzumab but not cetuximab. Overall, tumor-infiltrating CD3+ cell counts increased following treatment with both antibodies. A significant increase from baseline in CD3+/perforin+ cytotoxic T cells occurred only in the 700-mg imgatuzumab group (median 95% increase, P < 0.05). The most prominent decrease of EGFR-expressing cells was recorded after treatment with imgatuzumab (700 mg, -34.6%; 1400 mg, -41.8%). The post-treatment inflammatory tumor microenvironment was strongly related to baseline tumor-infiltrating immune cell density, and baseline levels of EGFR and pERK in tumor cells most strongly predicted therapeutic response. CONCLUSIONS: These pharmacodynamic observations and relationship with efficacy are consistent with the proposed mode of action of imgatuzumab combining efficient EGFR pathway inhibition with ADCC-related immune antitumor effects. CLINICAL TRIAL REGISTRATION NUMBER: NCT01046266 (ClinicalTrials.gov).

Cancer incidence in the wastewater treatment plant of a large chemical company.

OBJECTIVES: To evaluate cancer incidence among employees assigned to BASF's wastewater treatment plant. METHODS: We conducted a retrospective cohort study including 477 male employees who had ever worked in the facility for at least 1 year since the start of operations in 1974. Cancers were identified by review of occupational medical records and a standardized questionnaire completed by the participants or their next of kin. Confirmation through hospital records was sought for all reported cases after obtaining informed consent. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) were computed using comparison data provided by the Saarland Cancer Registry. Further comparisons were made between three different subgroups of employees, working in maintenance, wastewater processing, and sewage sludge treatment. RESULTS: A total of 50 cancers were observed (SIR 1.14, CI 0.85-1.51). Colorectal (1.14, 0.42-2.48), bronchial (1.40, 0.67-2.57) and prostate (1.15, 0.42-2.50) were the most frequently observed cancers. Five cases of bladder cancer were found in the total cohort (1.75, 0.57-4.09), with four of them occurring in the sewage sludge treatment area (6.82, 1.86-17.46). Allowing for a 10-year lag did not significantly change the results. CONCLUSIONS: The overall cancer experience among employees of the wastewater treatment plant was similar to that of the corresponding general population. The finding of an excess risk for bladder cancer in one subgroup of workers was unexpected with regard to the available literature. There is no straightforward explanation for this finding, and it may be due to chance. An extended follow-up of this cohort will take place after 5 years. Annual bladder cancer screening is offered to active and retired employees from this plant for the time being. The current working conditions and work practices have been re-assessed by occupational hygienists and deemed to be safe.

Correction of respiratory burst activity in X-linked chronic granulomatous cells to therapeutically relevant levels after gene transfer into bone marrow CD34+ cells.

Chronic granulomatous disease (CGD) is a disorder of the lymphohematopoietic system, whereby phagocytes of affected patients are unable to kill microorganisms. CGD is caused by a functional defect in the phagocytic nicotinamide adenine dinucleotide phosphatase (NADPH) oxidase (phox) enzyme complex, leading to a lack of microbicidal metabolites. As a therapeutic approach toward the predominant X-linked form of CGD, we have developed a bicistronic retroviral vector containing the coding sequences of gp91-phox and a cytoplasmically truncated version of the human low-affinity receptor for nerve growth factor (deltaLNGFR). Full reconstitution of superoxide-generating activity was achieved with this vector in a gp91-phox-deficient cell line. Using an optimized gene transfer protocol, up to 85% of the CD34+ cells obtained from the bone marrow of X-CGD patients were transduced. CD15+ cells differentiated in vitro from transduced X-CGD CD34+ cells showed correction of NADPH oxidase activity to 45-52% of normal levels whereas deltaLNGFR expression was found in 40-67% of the CD15+ cells. Moreover, immunoblots prepared from extracts of transduced CD15+ cells revealed gp91-phox protein levels similar to those found in neutrophils derived from normal CD34+ cells. Taking into consideration that superoxide production in only 5 to 10% of wild-type neutrophils is sufficient to protect X-CGD heterozygotes from serious infections, the results achieved in this study shows that for X-CGD patients a curative approach based on the genetic modification of hematopoietic stem/progenitor cells is feasible.

Assessment of 1,3-butadiene epidemiology studies.

Positive carcinogenicity studies in mice and rats have led to concerns that 1,3-butadiene may be carcinogenic in humans under exposure conditions that have existed in occupational settings and perhaps exist today. The principal settings of interest are the styrene-butadiene rubber (SBR) manufacturing industry, which uses large quantities of 1,3-butadiene, and the 1,3-butadiene monomer industry. The potential for 1,3-butadiene exposure is highest during monomer transfer operations and is lowest in finishing areas of polymerization plants where the polymer products are processed. Three large cohort mortality studies have been conducted in the SBR and monomer producing industries since 1980. These studies, which examined the mortality experience of over 17,000 men employed in one monomer and 10 SBR facilities, are the subject of this review. All but one of the facilities began operations during the early 1940s. The mortality experience observed within these employee cohorts is comparable to that seen in other long-term studies of men employed in the petroleum, chemical, and rubber industries for all causes of death, total malignant neoplasms, and for the specific cancers seen in excess in the toxicologic studies. This paper discusses discrepant findings observed in more detailed analyses within individual cohorts and among employment subgroups, as well as selected limitations of the particular studies. Additional efforts to refine 1,3-butadiene exposure categories are needed. Within the context of sample size limitations inherent in these studies, there is currently inadequate evidence to establish a relationship between cancer mortality outcomes and 1.3-butadiene exposure in humans.

Gene therapy of chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder which results from absence or malfunction of the respiratory burst oxidase normally expressed in neutrophils and other phagocytic leukocytes. Two-thirds of the patients are males hemizygous for mutations in the X-linked gene coding for gp91-phox. As a therapeutic approach towards the X-linked form of CGD bicistronic retroviral vectors containing the gp91-phox gene and a selectable marker gene were constructed. The ability of these vectors to restore NADPH oxidase activity was tested in a human myeloid leukemic cell line that is defective in superoxide production, as well as in primary CD34+ cells obtained from X-CGD patients. Under optimal conditions 80% of the CD34+ cells derived from bone marrow of one X-CGD patient were transduced. The level of superoxide production, in phagocytes derived from transduced cells was 68.9% of normal levels. Considering that low levels of superoxide generating activity are sufficient for normal host defense, the present experiments provide the basis for the development of a gene replacement therapy for the X-linked form of CGD.

Helicobacter pylori infection: prevalence and clinical relevance in a large company.

Although gastrointestinal (GI) illnesses account for considerable sick absenteeism, there have been few workplace studies of GI disorders. We determined the prevalence of Helicobacter pylori infection by serology and assessed its relation to upper GI tract complaints, personal ulcer history, and family history of stomach cancer in 6,143 employees (mean age, 40.4 years) at BASF's main chemical production facilities in Ludwigshafen, Germany. Employees were recruited during occupational health clinic visits (n = 4,488) and through broad communications efforts (n = 1,655). Participation among clinic attendees was 66%, and this recruitment method was particularly effective in reaching shift employees. Positive immunoglobulin G (IgG) serology (38.2%), ulcers (4.9%), nonulcer dyspepsia (20.4%), and a family history of stomach cancer (6.1%) were common occurrences in this work setting. Further diagnostic evaluation and eradication therapy was recommended for 795 employees (12.9%), based on a combination of positive serology and either upper GI tract complaints or family stomach cancer history, and has been completed for 541 employees. A weak but consistent association was seen between positive serology and cigarette smoking, and shift work was found to be associated with positive serology, but not with ulcer or nonulcer dyspepsia occurrence.

Mortality study of ethanol and isopropanol production workers at two facilities.

The mortality experience of alcohol process workers (N = 1031) from two chemical plants was followed from the early 1940s to 1983. Reported associations of the production of ethanol and isopropanol by the strong-acid process with upper respiratory tract cancers, heart disease, and lympho- and reticulosarcoma were tested with both external and internal comparisons. Excesses of cancers of the larynx, buccal cavity, and pharynx, based on very small numbers, were observed. There was one death due to sinus cancer. It could not be concluded that there were work-related effects on mortality due to heart disease or lympho- or reticulosarcoma. Workers assigned to the production of isopropanol by the weak-acid method showed no evidence of excess cancer mortality (0 observed, 1.9 expected cancer deaths). The absence of major risks among strong-acid workers can be explained by the initiation of engineering controls and health monitoring that took place after the original medical observations.

Health evaluation of employees occupationally exposed to methylene chloride.

General study design and environmental considerations. Scand j work environ health 9 (1983): suppl 1, 1-7. Recent concern regarding health hazards of methylene chloride stem primarily from the discovery of its metabolism to carboxyhemoglobin. In this report, a research program is described, the purpose of which was to assess potential health effects of methylene chloride exposure in an occupational setting. Particular attention was given to evaluating possible direct and carboxyhemoglobin-mediated effects on the hematopoietic and circulatory systems. The study involved one fiber production plant which used a methylene chloride/methanol mixture and acetone as solvents and a second fiber production plant that used acetone only. The research design included a retrospective cohort mortality study and several health evaluation studies, as well as an environmental assessment of the two plants. Industrial hygiene monitoring indicated that typical methylene chloride exposures ranged from an 8-h time-weighted average of 140 ppm in areas of low methylene chloride use to a corresponding average of 475 ppm in areas of high methylene chloride use and that methanol was present in about a one to ten ratio to methylene chloride. Acetone exposures in both plants ranged from 100 to over 1,000 ppm (time-weighted average).

Laboratory results for selected target organs in 138 individuals occupationally exposed to TCDD.

Blood specimens for dioxin congener analysis and clinical laboratory studies were recently obtained for 138 employees who had been potentially exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) following a 1953 trichlorophenol autoclave accident. Results for 34 clinical tests were regressed on three exposure measures (current TCDD concentration, log TCDD concentration back-calculated to the time of exposure, and chloracne status). Age, smoking status and body-mass-index were included as additional explanatory factors in the analyses. Positive associations were found between each of the exposure measures and both serum thyroxine (T4) and thyroxine binding globulin (TBG). Additional exposure-response associations were detected relative to several immune system parameters, erythrocyte sedimentation rate, platelet count and serum alkaline phosphatase. These data will be specifically helpful in interpreting the results of additional morbidity and mortality studies conducted within the same target population.

Vinyl chloride exposure in a controlled industrial environment. A long-term mortality experience in 594 employees.

Vinyl chloride has been associated recently with findings of angiosarcoma in animals and man. The present study examines the mortality experience of individuals occupationally exposed to vinyl chloride and lesser amounts of vinylidene chloride and other compounds. Employees were grouped into four exposure categories according to the highest levels of vinyl chloride exposure experienced for at least one month. Although no angiosarcomas were found and there were no deaths due to any liver malignancy, the observed malignancy deaths exceeded the expected among workers in the high-exposure category. Fewer than expected malignancy deaths were observed in the remaining exposure catergories.

Mortality experience of employees with occupational exposure to DBCP.

Concern about the carcinogenic potential of 1,2-dibromo-3-chloropropane(DBCP) has arisen recently, focusing on six organ sites: stomach, liver, kidney, lung, testes, and skin. To examine the mortality experience of persons potentially exposed, a cohort of 550 employees involved in production and formulation from 1957 to 1976 was defined. A total of 35 deaths was observed through 1979 (39.2 expected). No statistically significant excess was observed for any cause of death. No cancer deaths were noted for five of the hypothesized sites. For the lung cancer category, five deaths were observed (2.7 expected, P greater than .135), two of which occurred in a subgroup directly exposed for at least 1 yr (0.5 expected, P greater than .077). Aside from arsenicals exposure, potential confounding resulting from smoking or multiple chemical exposures could not be evaluated.

Mortality among individuals occupationally exposed to benzene.

The mortality experience of 594 individuals occupationally exposed to benzene was investigated using a retrospective cohort design. Three hundred thirty-five of the employees began working in benzene areas prior to 1950, which provided a sound data base from which to examine latency. Data derived from work histories and industrial hygiene records permitted estimation of exposure intensities and cumulative dosages for each employee. No mortalities directly attributable to benzene exposure were observed. Several cases of leukemia and other blood disorders were noted and discussed.

Health of workers exposed to 1, 1, 1,-trichloroethane: a matched-pair study.

An epidemiologic study of 151 matched pairs of employees was conducted in two adjacent textile plants, one of which used inhibited 1,1,1-trichloroethane as a general cleaning solvent. Employees in the study population had exposures to the solvent for 6 yrs or less at varying concentrations which were measured by breathing zone sampling and personal monitoring. While cardiovascular and hepatic observations were of primary interest, other health parameters were also studied. Application of sensitive statistical techniques and careful examination of all data did not reveal any clinically pertinent findings that were associated with exposure to 1,1,1-trichloroethane. The statistically significant associations that were observed between health measures and nonexposure factors emphasize the need to consider age, sex, race, and other variables in designing epidemiologic studies.

Mortality experience among Louisiana chemical manufacturing employees, 1957-1992.

A cohort mortality study was undertaken of persons ever employed at BASF's Geismar, Louisiana chemical manufacturing facilities for 3+ months prior to 1992. The 1,870 men and 263 women employees were traced through 1992 (99% follow-up) using employment and pension records, National Death Index searches, social security record matching, and credit bureau checks. Death certificates were obtained and coded for 92% of the 128 decedents. Overall and total cancer deaths among short-term ( < 10 years of site employment) and long-term hourly and salaried employees were fewer than expected based on comparisons to US general population death rates. Deaths due to external causes were higher than expected among short-term hourly employees (23 observed compared to 16 expected deaths). Among all employees, three accidental deaths occurred at work, the most recent in 1981. Four deaths each, due to urinary and brain cancers, exceeded expectation; however, there was no pattern of job assignments suggesting a work-related etiology for these occurrences.

Progress and prospects: gene therapy clinical trials (part 1).

Over the last two decades gene therapy has moved from preclinical to clinical studies for many diseases ranging from single gene disorders such as cystic fibrosis and Duchenne muscular dystrophy, to more complex diseases such as cancer and cardiovascular disorders. Gene therapy for severe combined immunodeficiency (SCID) is the most significant success story to date, but progress in many other areas has been significant. We asked 20 leaders in the field succinctly to summarize and comment on clinical gene therapy research in their respective areas of expertise and these are published in two parts in the Progress and Prospect series.

Importance of the study protocol in epidemiologic research.

The overall quality of an epidemiologic research project depends on how well both the design and execution phases of the project have been accomplished. The written prestudy protocol, by serving as a bridge between these two project phases, plays a pivotal role in determining the success of the total research effort. The study protocol can contribute to improved observational research in four key areas. Arguments are presented for enhancing the scientific integrity of observational studies and for providing better study documentation, efficiency, and communications, all through careful prestudy planning.

A mortality study of a research, engineering, and metal fabrication facility in western New York State.

The mortality experience of 8,146 male employees of a research, engineering, and metal fabrication facility in Tonawanda, New York state was examined from 1946 to 1981. Potential workplace exposures included welding fumes, cutting oils, asbestos, organic solvents, and environmental ionizing radiation, as the result of disposal of wastes during the Manhattan Project of World War II. External comparisons with the US male population were supplemented by regional comparisons. For the total cohort, deficits were observed for all causes of death (standardized mortality ratio (SMR) = 87) and most non-cancer causes. The observed number of cancer deaths was close to expected (SMR = 99). There was an excess of connective and soft tissue cancer deaths, most notably in hourly employees hired prior to 1946. Among all hourly employees, there was an excess of respiratory cancer, which did not appear to be associated with length of employment. Mesothelioma was recorded as the cause of death for three decedents, two of whom were hourly employees who worked in production areas with high potential for asbestos exposure. The standardized mortality ratio for cirrhosis of the liver was elevated among long-term hourly employees hired prior to 1946. The roles of carbon tetrachloride exposure in the 1940s and alcohol consumption are discussed as possible contributory risk factors for the cirrhosis findings. The data do not provide evidence of radiation-induced cancers within this employee population.

A review of medical surveillance records of employees exposed to ethyleneamines.

A review of medical surveillance records was undertaken for 197 personnel who had been assigned to an ethyleneamines (EA) production unit for one or more months between 1947 and 1983. Dispensary visit reports were examined relative to EA and other chemical exposures, medical records were reviewed for allergy and asthma histories, spirometry data were evaluated, and the mortality experience of these employees was studied relative to exposure status. All findings were evaluated in reference to a comparable group of employees who did not work in plant areas where contact with EA was likely. Among 75 persons reporting EA exposures, 7 definite and 8 suspect cases of respiratory sensitization were identified. Similarly, there were 23 definite and 17 suspect cases of skin sensitization. Pulmonary function did not differ between study and referent groups and was unrelated to both EA assignment duration and skin or respiratory sensitization. There were no indications of increased mortality in the study group. Careful selection of employees for assignment to this unit may have occurred by plant physicians, who were aware of the potential sensitizing properties of EA.